CVS Physiology PDF

Copyright © 2018 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written per...

Copyright © 2018 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-1-26-002612-2 MHID: 1-26-002612-4 The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-002611-5, MHID: 1-26-002611-6. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. 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This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.  Contents Preface Chapter 1 Overview of the Cardiovascular System Objectives Evolution and Homeostatic Role of the Cardiovascular System Overall Design of the Cardiovascular System The Basic Physics of Blood Flow Material Transport by Blood Flow The Heart The Vasculature Blood Perspectives Chapter 2 Characteristics of Cardiac Muscle Cells Objectives Electrical Activity of Cardiac Muscle Cells Mechanical Activity of the Heart Relating Cardiac Muscle Cell Mechanics to Ventricular Function Perspectives Chapter 3 The Heart Pump Objectives Cardiac Cycle Determinants of Cardiac Output Influences on Stroke Volume Summary of Determinants of Cardiac Output Summary of Sympathetic Neural Influences on Cardiac Function Cardiac Energetics Perspectives Chapter 4 Measurements of Cardiac Function Objectives Measurement of Mechanical Function Measurement of Cardiac Excitation—The Electrocardiogram Perspectives Chapter 5 Cardiac Abnormalities Objectives Electrical Abnormalities and Arrhythmias Cardiac Valve Abnormalities Perspectives Chapter 6 The Peripheral Vascular System Objectives Transcapillary Transport Resistance and Flow in Networks of Vessels Normal Conditions in the Peripheral Vasculature Measurement of Arterial Pressure Determinants of Arterial Pressure Perspectives Chapter 7 Vascular Control Objectives Vascular Smooth Muscle Control of Arteriolar Tone Control of Venous Tone Summary of Primary Vascular Control Mechanisms Vascular Control in Specific Organs Perspectives Chapter 8 Hemodynamic Interactions Objectives Key System Components Central Venous Pressure: An Indicator of Circulatory Status Perspectives Chapter 9 Regulation of Arterial Pressure Objectives Short-Term Regulation of Arterial Pressure Long-Term Regulation of Arterial Pressure Perspectives Chapter 10 Cardiovascular Responses to Physiological Stresses Objectives Primary Disturbances and Compensatory Responses Effect of Respiratory Activity Effect of Gravity Effect of Exercise Normal Cardiovascular Adaptations Perspectives Chapter 11 Cardiovascular Function in Pathological Situations Objectives Circulatory Shock Cardiac Disturbances Hypertension Perspectives Answers to Study Questions Appendix A Appendix B Appendix C Appendix D Appendix E Index  Preface In this our final edition as primary authors of this text, we have continued our penchant of focusing on the big picture of how and why the cardiovascular system operates as it does. Our firm belief is that to evaluate the importance and consequences of specific details it is essential to appreciate where they fit in the big picture. The core idea is for students not to get lost in the forest for the trees. The same approach will serve practitioners well throughout their careers as they evaluate new information as it arises. The cardiovascular system is a circular interconnection of many individual components—each with its own rules of operation that must be followed. But in the intact system, the individual components are forced to interact with each other. A change in the operation of any one component has repercussions throughout the system. Understanding such interactions is essential to developing a big picture of how the intact system behaves. Only then can one fully understand all the consequences of malfunctions in particular components and/or particular clinical interventions. This ninth edition includes some recent, new findings as well as a newly added emphasis on cardiovascular energetics. The latter is a result of our recent realization that maximizing energy efficiency to limit the workload on the heart is an important part of the overall plan. As always, we express sincere thanks to our families for their continual support of our efforts, and to our mentors, colleagues, and students for all they have taught us over the years. Also, these authors would like to thank each other for the uncountable but fruitful hours we have spent arguing about how the cardiovascular system operates from our own (and often very different perspectives). David E. Mohrman, PhD Lois Jane Heller, PhD Overview of the Cardiovascular 1 System OBJECTIVES The student understands the homeostatic role of the cardiovascular system, the basic principles of cardiovascular transport, and the basic structure and function of the components of the system: Defines homeostasis. Identifies the major body fluid compartments and states the approximate volume of each. Lists 3 conditions, provided by the cardiovascular system, that are essential for regulating the composition of interstitial fluid (i.e., the internal environment). Predicts the relative changes in flow through a tube caused by changes in tube length, tube radius, fluid viscosity, and pressure difference. Uses the Fick principle to describe convective transport of substances through the CV system and to calculate a tissue’s rate of utilization (or production) of a substance. Identifies the chambers and valves of the heart and describes the pathway of blood flow through the heart. Defines cardiac output and identifies its 2 determinants. Describes the site of initiation and pathway of action potential propagation in the heart. States the relationship between ventricular filling and cardiac output (the Starling law of the heart) and describes its importance in the control of cardiac output. Identifies the distribution of sympathetic and parasympathetic nerves in the heart and lists the basic effects of these nerves on the heart.  Lists the 5 factors essential to proper ventricular pumping action. Lists the major different types of vessels in a vascular bed and describes the morphological differences among them. Describes the basics and functions of the different vessel types. Identifies the major mechanisms in vascular resistance control and blood flow distribution. Describes the basic composition of the fluid and cellular portions of blood. EVOLUTION AND HOMEOSTATIC ROLE OF THE CARDIOVASCULAR SYSTEM All living organisms require outside energy sources to survive. Indeed, Darwin deduced his evolutionary concepts largely on observations of external adaptations that evolved in different organisms to exploit particular unique sources of “food” energy. Clearly one strong evolutionary force has been to maximize the ability to obtain outside energy. In the big picture of “survival of the fittest,” equally important to obtaining outside energy is making efficient use of it once it is obtained. Therefore, we contend that developing energy-efficient mechanisms to accomplish all internal tasks necessary for successful life has also been a strong evolutionary force and probably applies to all “internal” processes. In this text, we focus on how the design and operation of the human cardiovascular system has evolved to accomplish its essential tasks with a minimum of energy expenditure. A 19th-century French physiologist, Claude Bernard (1813–1878), first recognized that all higher organisms actively and constantly strive to prevent the external environment from upsetting the conditions necessary for life within the organism. Thus, the temperature, oxygen concentration, pH, ionic composition, osmolarity, and many other important variables of our internal environment are closely controlled. This process of maintaining the “constancy” of our internal environment has come to be known as homeostasis. To aid in this task, an elaborate material transport network, the cardiovascular system, has evolved. Three compartments of watery fluids, known collectively as the total body water, account for approximately 60% of body weight in a normal adult. This water is distributed among the intracellular, interstitial, and plasma compartments, as indicated in Figure 1–1. Note that about two- thirds of our body water is contained within cells and communicates with the interstitial fluid across the plasma membranes of cells. Of the fluid that is outside cells (i.e., extracellular fluid), only a small amount, the plasma volume, circulates within the cardiovascular system. Total circulating blood volume is larger than that of blood plasma, as indicated in Figure 1– 1, because blood also contains suspended blood cells that collectively occupy approximately 40% of its volume. However, it is the circulating plasma that directly interacts with the interstitial fluid of body organs across the walls of the capillary vessels. The interstitial fluid is the immediate environment of individual cells. (It is the “internal environment” referred to by Bernard.) These cells must draw their nutrients from and release their products into the interstitial fluid. The interstitial fluid cannot, however, be considered a large reservoir for nutrients or a large sink for metabolic products, because its volume is less than half that of the cells that it serves. The well-being of individual cells therefore depends heavily on the homeostatic mechanisms that regulate the composition of the interstitial fluid. This task is accomplished by continuously exposing the interstitial fluid to “fresh” circulating plasma fluid. Figure 1–1. Major body fluid compartments with average volumes indicated for a normal 70-kg adult human. Total body water is approximately 60% of body weight. As blood passes through capillaries, solutes exchange between plasma and interstitial fluid by the process of diffusion. The net result of transcapillary diffusion is always that the interstitial fluid tends to take on the composition of the incoming blood. If, for example, potassium ion concentration in the interstitium of a particular skeletal muscle was higher than that in the plasma entering the muscle, then potassium would diffuse into the blood as it passes through the muscle’s capillaries. Because this removes potassium from the interstitial fluid, its potassium ion concentration would decrease. It would stop decreasing when the net movement of potassium into capillaries no longer occurs, that is, when the concentration of the interstitial fluid reaches that of incoming plasma.  Three conditions are essential for this circulatory mechanism to effectively control the composition of the interstitial fluid: (1) there must be adequate blood flow through the tissue capillaries; (2) the chemical composition of the incoming (or arterial) blood must be controlled to be that which is optimal in the interstitial fluid; and (3) diffusion distances between plasma and tissue cells must be short. Figure 1–1 shows how the cardiovascular transport system operates to accomplish these tasks. Diffusional transport within tissues occurs over extremely small distances because no cell in the body is located farther than approximately 10 μm from a capillary. Over such microscopic distances, diffusion is a very rapid process that can move huge quantities of material. Diffusion, however, is a very poor mechanism for moving substances from the capillaries of an organ, such as the lungs, to the capillaries of another organ that may be 1 m or more distant. Consequently, substances are transported between organs by the process of convection, by which the substances easily move along with blood flow because they are either dissolved or contained within blood. The relative distances involved in cardiovascular transport are not well illustrated in Figure 1–1. If the figure was drawn to scale, with 1 inch representing the distance from capillaries to cells within a calf muscle, then the capillaries in the lungs would have to be located about 15 miles away! OVERALL DESIGN OF THE CARDIOVASCULAR SYSTEM The overall functional arrangement of the cardiovascular system is illustrated in Figure 1–2. Because a functional rather than an anatomical viewpoint is expressed in this figure, the role of heart appears in 3 places: as the right heart pump, as the left heart pump, and as the heart muscle tissue. It is common practice to view the cardiovascular system as (1) the pulmonary circulation, composed of the right heart pump and the lungs, and (2) the systemic circulation, in which the left heart pump supplies blood to the systemic organs (all structures except the gas exchange portion of the lungs). The pulmonary and systemic circulations are arranged in series, that is, one after the other. Consequently, both the right and left hearts must pump an identical volume of blood per minute. This amount is called the cardiac output. As indicated in Figure 1–2, most systemic organs are functionally arranged in parallel (i.e., side by side) within the cardiovascular system. There are 2 important consequences of this parallel arrangement. First, nearly all systemic organs receive blood of identical composition—that which has just left the lungs and is known as arterial blood. Second, the flow through any one of the systemic organs can be controlled independently of the flow through the other organs. Thus, for example, the cardiovascular response to whole-body exercise can involve increased blood flow through some organs, decreased blood flow through others, and unchanged blood flow through yet others. Many of the organs in the body help perform the task of continually reconditioning the blood circulating in the cardiovascular system. Key roles are played by organs, such as the lungs, that communicate with the external environment. As is evident from the arrangement shown in Figure 1–2, any blood that has just passed through a systemic organ returns to the right heart and is pumped through the lungs, where oxygen and carbon dioxide are exchanged. Thus, the blood’s gas composition is always reconditioned immediately after leaving a systemic organ. Figure 1–2. Cardiovascular circuitry, indicating the percentage distribution of cardiac output to various organ systems in a resting individual. Like the lungs, many of the systemic organs also serve to recondition the composition of blood, although the flow circuitry precludes their doing so each time the blood completes a single circuit. The kidneys, for example, continually adjust the electrolyte composition of the blood passing through them. Because the blood conditioned by the kidneys mixes freely with all the circulating blood and because electrolytes and water freely pass through most capillary walls, the kidneys control the electrolyte balance of the entire internal environment. To achieve this, it is necessary that a given unit of blood pass often through the kidneys. In fact, the kidneys normally receive about one-fifth of the cardiac output under resting conditions. This greatly exceeds the amount of flow that is necessary to supply the nutrient needs of the renal tissue. This situation is common to organs that have a blood-conditioning function. Blood-conditioning organs can also withstand, at least temporarily, severe reduction of blood flow. Skin, for example, can easily tolerate a large reduction in blood flow when it is necessary to conserve body heat. Most of the large abdominal organs also fall into this category. The reason is simply that because of their blood-conditioning functions, their normal blood flow is far in excess of that necessary to maintain their basal metabolic needs. The brain, heart muscle, and skeletal muscles typify organs in which blood flows solely to supply the metabolic needs of the tissue. They do not recondition the blood for the benefit of any other organ. Normally, the blood flow to the brain and the heart muscle is only slightly greater than that required for their metabolism; hence, they do not tolerate blood flow interruptions well. Unconsciousness can occur within a few seconds after stoppage of cerebral flow, and permanent brain damage can occur in as little as 4 minutes without flow. Similarly, the heart muscle ( myocardium) normally consumes approximately 75% of the oxygen supplied to it, and the heart’s pumping ability begins to deteriorate within beats of a coronary flow interruption. As we shall see later, the task of providing adequate blood flow to the brain and the heart muscle receives a high priority in the overall operation of the cardiovascular system. Cardiac muscle must do physical work to move blood through the circulatory system. Note in Figure 1–2 that the cardiac muscle itself requires only about 3% of all the blood it is pumping to sustain its own operation. The clear implication is that the heart has evolved into a very efficient pump. Within any given tissue, the blood flow required to maintain local homeostasis is directly related to its current cellular metabolic rate. Under challenges of daily life, metabolic activity of many individual organs can change dramatically from situation to situation. For example, metabolic rate of maximally active skeletal muscle can be 50 times that of its inactive (resting) rate. Thus, it is essential for the cardiovascular system to rapidly adapt to ever-changing needs in the body. As far as the heart is concerned, the bottom line is how much blood flow it must produce in different situations regardless of where that total flow is directed. Cardiac output in a resting human adult is about 5 to 6 L/min (80 gallons/h, 2000 gallons/day!) and can increase to 3 to 4 times that amount during maximal exercise. Presumably, the cardiovascular system has evolved to efficiently operate over that range. THE BASIC PHYSICS OF BLOOD FLOW One of the most important keys to comprehending how the cardiovascular system operates is to have a thorough understanding of the relationship among the physical factors that determine the rate of fluid flow through a tubular vessel. The tube depicted in Figure 1–3 might represent a segment of any vessel in the body. It has a certain length ( L) and a certain internal radius ( r) through which blood flows. Fluid flows through the tube only when the pressures in the fluid at the inlet and outlet ends ( P i and P o) are unequal, that is, when there is a pressure difference (Δ P) between the ends. Pressure differences supply the driving force for flow. Because friction develops between the moving fluid and the stationary walls of a tube, vessels tend to resist fluid movement through them. This vascular resistance is a measure of how difficult it is to make fluid flow through the tube, that is, how much of a pressure difference it takes to cause a certain flow. The all-important relationship among flow, pressure difference, and resistance is described by the basic flow equation as follows: or where = flow rate (volume/time), Δ P = pressure difference (mm Hg 1), and R = resistance to flow (mm Hg × time/volume). Figure 1–3. Factors influencing fluid flow through a tube. The basic flow equation may be applied not only to a single tube but also to complex networks of tubes, for example, the vascular bed of an organ or the entire systemic system. The flow through the brain, for example, is determined by the difference in pressure between cerebral arteries and veins divided by the overall resistance to flow through the vessels in the cerebral vascular bed. It should be evident from the basic flow equation that there are only 2 ways in which blood flow through any organ can be changed: (1) by changing the pressure difference across its vascular bed or (2) by changing its vascular resistance. Most often, it is changes in an organ’s vascular resistance that cause the flow through the organ to change. From the work of the French physician Jean Leonard Marie Poiseuille (1799–1869), who performed experiments on fluid flow through small glass capillary tubes, it is known that the resistance to flow through a cylindrical tube depends on several factors, including the radius and length of the tube and the viscosity of the fluid flowing through it. These factors influence resistance to flow as follows: where r = inside radius of the tube, L = tube length, and η = fluid viscosity. Note especially that the internal radius of the tube is raised to the fourth power in this equation. Thus, even small changes in the internal radius of a tube have a huge influence on its resistance to flow. For example, halving the inside radius of a tube will increase its resistance to flow by 16-fold. The preceding 2 equations may be combined into one expression known as the Poiseuille equation, which includes all the terms that influence flow through a cylindrical vessel: Again, note that flow occurs only when a pressure difference exists. (If Δ P = 0, then flow = 0.) It is not surprising then that arterial blood pressure is an extremely important and carefully regulated cardiovascular variable. Also note once again that for any given pressure difference, tube radius has a very large influence on the flow through a tube. It is logical, therefore, that organ blood flows are regulated primarily through changes in the radii of vessels within organs. Although vessel length and blood viscosity are factors that influence vascular resistance, they are not variables that can be easily manipulated for the purpose of moment-to- moment control of blood flow. In regard to the overall cardiovascular system, as depicted in Figures 1–1 and 1–2, one can conclude that blood flows through the vessels within an organ only because a pressure difference exists between the blood in the arteries supplying the organ and the veins draining it. The primary job of the heart pump is to keep the pressure within arteries higher than that within veins. Normally, the average pressure in systemic arteries is approximately 100 mm Hg, and the average pressure in systemic veins is approximately 0 mm Hg. Therefore, because the pressure difference (Δ P) is nearly identical across all systemic organs, cardiac output is distributed among the various systemic organs, primarily on the basis of their individual resistances to flow. Because blood preferentially flows along paths of least resistance, organs with relatively low resistance naturally receive relatively high flow. MATERIAL TRANSPORT BY BLOOD FLOW Substances are carried between organs within the cardiovascular system by the process of convective transport, the simple process of being swept along with the flow of the blood in which they are contained. The rate at which a substance (X) is transported by this process depends solely on the concentration of the substance in the blood and the blood flow rate.  where = rate of transport of X (mass/time), = blood flow rate (volume/time), and [ X] = concentration of X in blood (mass/volume). It is evident from the preceding equation that only 2 methods are available for altering the rate at which a substance is carried to an organ: (1) a change in the blood flow rate through the organ or (2) a change in the arterial blood concentration of the substance. The preceding equation might be used, for example, to calculate how much oxygen is carried to a certain skeletal muscle each minute. Note, however, that this calculation would not indicate whether the muscle actually used the oxygen carried to it. The Fick Principle One can extend the convective transport principle to calculate the rate at which a substance is being removed from (or added to) the blood as it passes through an organ. To do so, one must simultaneously consider the rate at which the substance is entering the organ in the arterial blood and the rate at which the substance is leaving the organ in the venous blood. The basic logic is simple. For example, if something goes into an organ in arterial blood and does not come out on the other side in venous blood, it must have left the blood and entered the tissue within the organ. This concept is referred to as the Fick principle (Adolf Fick, a German physician, 1829–1901) and may be formally stated as follows: where tc = transcapillary efflux rate of X, = blood flow rate, and [ X] a,v = arterial and venous concentrations of X. The Fick principle is useful because it offers a practical method to deduce a tissue’s steady-state rate of consumption (or production) of any substance. To understand why this is so, one further step in logic is necessary. Consider, for example, what possibly can happen to a substance that enters a tissue from the blood. It can either (1) increase the concentration of itself within the tissue or (2) be metabolized (i.e., converted into something else) within the tissue. A steady state implies a stable situation wherein nothing (including the substance’s tissue concentration) is changing with time. Therefore, in the steady state, the rate of the substance’s loss from blood within a tissue must equal its rate of metabolism within that tissue. THE HEART Pumping Action The heart lies in the center of the thoracic cavity and is suspended by its attachments to the great vessels within a thin fibrous sac called the pericardium. A small amount of fluid in the sac lubricates the surface of the heart and allows it to move freely during contraction and relaxation. Blood flow through all organs is passive and occurs only because arterial pressure is kept higher than venous pressure by the pumping action of the heart. The right heart pump provides the energy necessary to move blood through the pulmonary vessels, and the left heart pump provides the energy to move blood through the systemic organs. The pathway of blood flow through the chambers of the heart is indicated in Figure 1–4. Venous blood returns from the systemic organs to the right atrium via the superior and inferior venae cavae. This “venous” blood is deficient in oxygen because it has just passed through systemic organs that all extract oxygen from blood for their metabolism. It then passes through the tricuspid valve into the right ventricle and from there it is pumped through the pulmonic valve into the pulmonary circulation via the pulmonary arteries. Within the capillaries of the lung, blood is “reoxygenated” by exposure to oxygen-rich inspired air. Oxygenated pulmonary venous blood flows in pulmonary veins to the left atrium and passes through the mitral valve into the left ventricle. From there it is pumped through the aortic valve into the aorta to be distributed to the systemic organs. Figure 1–4. Pathway of blood flow through the heart. Although the gross anatomy of the right heart pump is somewhat different from that of the left heart pump, the pumping principles are identical. Each pump consists of a ventricle, which is a closed chamber surrounded by a muscular wall, as illustrated in Figure 1–5. The valves are structurally designed to allow flow in only one direction and passively open and close in response to the direction of the pressure differences across them. Ventricular pumping action occurs because the volume of the intraventricular chamber is cyclically changed by rhythmic and synchronized contraction and relaxation of the individual cardiac muscle cells that lie in a circumferential orientation within the ventricular wall. 2 When the ventricular muscle cells are contracting, they generate a circumferential tension in the ventricular walls that causes the pressure within the chamber to increase. As soon as the ventricular pressure exceeds the pressure in the pulmonary artery (right pump) or aorta (left pump), blood is forced out of the chamber through the outlet valve, as shown in Figure 1–5. This phase of the cardiac cycle during which the ventricular muscle cells are contracting is called systole. Because the pressure is higher in the ventricle than in the atrium during systole, the inlet or atrioventricular (AV) valve is closed. When the ventricular muscle cells relax, the pressure in the ventricle falls below that in the atrium, the AV valve opens, and the ventricle refills with blood, as shown on the right side in Figure 1–5. This portion of the cardiac cycle is called diastole. The outlet valve is closed during diastole because arterial pressure is greater than intraventricular pressure. After the period of diastolic filling, the systolic phase of a new cardiac cycle is initiated. Figure 1–5. Ventricular pumping action. The amount of blood pumped per minute from each ventricle (the cardiac output, CO) is determined by the volume of blood ejected per beat (the stroke volume, SV) and the number of heartbeats per minute (the heart rate, HR) as follows:  It should be evident from this relationship that all influences on cardiac output must act through changes in either the heart rate or the stroke volume. An important implication of the above is that the volume of blood that the ventricle pumps with each heartbeat (i.e., the stroke volume, SV) must equal the blood volume inside the ventricle at the end of diastole ( end- diastolic volume, EDV) minus ventricular volume at the end of systole ( end-systolic volume, ESV). That is, SV = EDV — ESV Thus, stroke volume can only be changed by changes in EDV and/or ESV. The implication for the bigger picture is that cardiac output can only be changed by changes in HR, EDV, and/or ESV. Cardiac Excitation Efficient pumping action of the heart requires a precise coordination of the contraction of millions of individual cardiac muscle cells. Contraction of each cell is triggered when an electrical excitatory impulse ( action potential) sweeps over its membrane. Proper coordination of the contractile activity of the individual cardiac muscle cells is achieved primarily by the conduction of action potentials from one cell to the next via gap junctions that connect all cells of the heart into a functional syncytium (i.e., acting as one synchronous unit). In addition, muscle cells in certain areas of the heart are specifically adapted to control the frequency of cardiac excitation, the pathway of conduction, and the rate of the impulse propagation through various regions of the heart. The major components of this specialized excitation and conduction system are shown in Figure 1–6. These include the sinoatrial node (SA node), the atrioventricular node (AV node), the bundle of His, and the right and left bundle branches made up of specialized cells called Purkinje fibers. The SA node contains specialized cells that normally function as the heart’s pacemaker and initiate the action potential that is conducted through the heart. The AV node contains slowly conducting cells that normally function to create a slight delay between atrial contraction and ventricular contraction. The Purkinje fibers are specialized for rapid conduction and ensure that all ventricular cells contract at nearly the same instant. The overall message is that HR is normally controlled by the electrical activity of the SA nodal cells. The rest of the conduction system ensures that all the rest of the cells in the heart follow along in proper lockstep for efficient pumping action. Figure 1–6. Electrical conduction system of the heart. Control of Cardiac Output A UTONOMIC N EURAL I NFLUENCES Although the heart can inherently beat on its own, cardiac function can be influenced profoundly by neural inputs from both the sympathetic and parasympathetic divisions of the autonomic nervous system. These inputs allow us to modify cardiac pumping as is appropriate to meet changing homeostatic needs of the body. All portions of the heart are richly innervated by adrenergic sympathetic fibers. When active, these sympathetic nerves release norepinephrine (noradrenaline) on cardiac cells. Norepinephrine interacts with β 1-adrenergic receptors on cardiac muscle cells to increase the heart rate, increase the action potential conduction velocity, and increase the force of contraction and rates of contraction and relaxation. Overall, sympathetic activation acts to increase cardiac pumping. Cholinergic parasympathetic nerve fibers travel to the heart via the vagus nerve and innervate the SA node, the AV node, and the atrial muscle. When active, these parasympathetic nerves release acetylcholine on cardiac muscle cells. Acetylcholine interacts with muscarinic receptors on cardiac muscle cells to decrease the heart rate (SA node) and decrease the action potential conduction velocity (AV node). Parasympathetic nerves may also act to decrease the force of contraction of atrial (not ventricular) muscle cells. Overall, parasympathetic activation acts to decrease cardiac pumping. Usually, an increase in parasympathetic nerve activity is accompanied by a decrease in sympathetic nerve activity, and vice versa. D IASTOLIC F ILLING: THE S TARLING L AW OF THE H EART One of the most fundamental causes of variations in stroke volume was described by William Howell in 1884 and by Otto Frank in 1894 and formally stated by E. H. Starling in 1918. These investigators demonstrated that, with other factors being equal, if cardiac filling increases during diastole, the volume ejected during systole also increases. As a consequence, and as illustrated in Figure 1–7, stroke volume increases nearly in proportion to increases in end-diastolic volume. This phenomenon is commonly referred to as the Starling law of the heart. In a subsequent chapter, we will describe how the Starling law is a direct consequence of the intrinsic mechanical properties of cardiac muscle cells. However, knowing the mechanisms behind the Starling law is not ultimately as important as appreciating its consequences. The primary consequence is that stroke volume (and therefore cardiac output) is strongly influenced by cardiac filling during diastole. Therefore, we shall later pay particular attention to the factors that affect cardiac filling and how they participate in the normal regulation of cardiac output. Figure 1–7. The Starling law of the heart. Requirements for Effective Operation For effective efficient ventricular pumping action, the heart must be functioning properly in 5 basic respects: 1. The contractions of individual cardiac muscle cells must occur at regular intervals and be synchronized (not arrhythmic). 2. The valves must open fully (not stenotic). 3. The valves must not leak (not insufficient or regurgitant). 4. The muscle contractions must be forceful (not failing). 5. The ventricles must fill adequately during diastole. In the subsequent chapters, we will study in detail how these requirements are met in the normal heart. Moreover, we will describe how failures in any of these respects lead to distinctly different, clinically relevant, pathologies and symptoms. THE VASCULATURE Blood that is ejected into the aorta by the left heart passes consecutively through many different types of vessels before it returns to the right heart. As illustrated in Figure 1–8, the major vessel classifications are arteries, arterioles, capillaries, venules, and veins. These consecutive vascular segments are distinguished from one another by differences in their physical dimensions, morphological characteristics, and function. One thing that all these vessels have in common is that they are lined with a contiguous single layer of endothelial cells. In fact, this is true for the entire circulatory system including the heart chambers and even the valve leaflets. Vessel Characteristics Some representative physical characteristics of these major vessel types are shown in Figure 1–8. It should be realized, however, that the vascular bed is a continuum and that the transition from one type of vascular segment to another does not occur abruptly. The total cross-sectional area through which blood flows at any particular level in the vascular system is equal to the sum of the cross-sectional areas of all the individual vessels arranged in parallel at that level. The number and total cross-sectional area values presented in Figure 1–8 are estimates for the entire systemic circulation. Arteries are thick-walled vessels that contain, in addition to some smooth muscle, a large component of elastin and collagen fibers. Primarily because of the elastin fibers, which can stretch to twice their unloaded length, arteries can expand under increased pressure to accept and temporarily store some of the blood ejected by the heart during systole and then, by passive recoil, supply this blood to the organs downstream during diastole. The aorta is the largest artery and has an internal (luminal) diameter of approximately 25 mm. Arterial diameter decreases with each consecutive branching, and the smallest arteries have diameters of approximately 0.1 mm. The consecutive arterial branching pattern causes an exponential increase in arterial numbers. Thus, although individual vessels get progressively smaller, the total cross-sectional area available for blood flow within the arterial system increases to several fold that in the aorta. Arteries are often referred to as conduit vessels because they have relatively low and unchanging resistance to flow. Figure 1–8. Structural characteristics of the peripheral vascular system. Arterioles are smaller and structured differently than arteries. In proportion to lumen size, arterioles have much thicker walls with more smooth muscle and less elastic material than do arteries. Because arterioles are so muscular, their diameters can be actively changed to regulate the blood flow through peripheral organs. Despite their minute size, arterioles are so numerous that in parallel their collective cross-sectional area is much larger than that at any level in arteries. Arterioles are often referred to as resistance vessels because of their high and changeable resistance, which regulates peripheral blood flow through individual organs. Capillaries are the smallest vessels in the vasculature. In fact, red blood cells with diameters of 7 μm must deform to pass through them. The capillary wall consists of a single layer of endothelial cells that separates the blood from the interstitial fluid by only approximately 1 μm. Capillaries contain no smooth muscle and thus lack the ability to change their diameters actively. They are so numerous that the total collective cross-sectional area of all the capillaries in systemic organs is more than 1000 times that of the root of the aorta. Given that capillaries are approximately 0.5 mm in length, the total surface area available for exchange of material between blood and interstitial fluid can be calculated to exceed 100 m 2. For obvious reasons, capillaries are viewed as the exchange vessels of the cardiovascular system. In addition to the transcapillary diffusion of solutes that occurs across these vessel walls, there can sometimes be net movements of fluid (volume) into and/or out of capillaries. For example, tissue swelling ( edema) is a result of net fluid movement from plasma into the interstitial space. After leaving capillaries, blood is collected in venules and veins and returned to the heart. Venous vessels have very thin walls in proportion to their diameters. Their walls contain smooth muscle, and their diameters can actively change. Because of their thin walls, venous vessels are quite distensible. Therefore, their diameters change passively in response to small changes in transmural distending pressure (i.e., the difference between the internal and external pressures across the vessel wall). Venous vessels, especially the larger ones, also have one-way valves that prevent reverse flow. As will be discussed later, these valves are especially important in the cardiovascular system’s operation during standing and during exercise. It turns out that peripheral venules and veins normally contain more than 50% of the total blood volume. Consequently, they are commonly thought of as the capacitance vessels. More importantly, changes in venous volume greatly influence cardiac filling and therefore cardiac pumping. Thus, peripheral veins actually play an extremely important role in controlling cardiac output. Control of Blood Vessels Blood flow through individual vascular beds is profoundly influenced by changes in the activity of sympathetic nerves innervating arterioles. These nerves release norepinephrine at their endings that interacts with α - adrenergic receptors on the smooth muscle cells to cause contraction and thus arteriolar constriction. The reduction in arteriolar diameter increases vascular resistance and decreases blood flow. These neural fibers provide the most important means of reflex control of vascular resistance and organ blood flow. Arteriolar smooth muscle is also very responsive to changes in the local chemical conditions within an organ that accompany changes in the metabolic rate of the organ. For reasons to be discussed later, increased tissue metabolic rate leads to arteriolar dilation and increased tissue blood flow. Venules and veins are also richly innervated by sympathetic nerves and constrict when these nerves are activated. The mechanism is the same as that involved with arterioles. Thus, increased sympathetic nerve activity is accompanied by decreased venous volume. The importance of this phenomenon is that venous constriction tends to increase cardiac filling and therefore cardiac output via the Starling law of the heart. To the best of our knowledge, there is no important neural or local metabolic control of either arterial or capillary vessel tone or diameter. Overall Vascular Function In essence, the bulk of the vascular system is simply the network of “pipes” necessary to route blood flow from the heart through capillary beds in organs throughout the body and then collect it again to return it to the heart. Because blood is a viscous fluid, there is an unavoidable energy loss (to heat via fluid friction) as it flows through any vessel. Thus, there is an energy cost to just distributing the blood throughout the body. This energy loss as blood moves through the vasculature is important because it determines how much work the heart must do to produce that flow in the first place. There are many possible plumbing schemes (e.g., various combinations of vessels of different diameters, lengths, and branching patterns) that could accomplish the goal of distributing blood to capillary beds throughout the body. However, some would do so with less frictional energy loss than others. We contend that the vascular system has evolved to distribute the cardiac output with minimal energy loss in the process. BLOOD Blood is a complex fluid that serves as the medium for transporting substances between the tissues of the body and performs a host of other functions as well. Normally, approximately 40% of the volume of whole blood is occupied by blood cells that are suspended in the watery fluid, plasma, which accounts for the rest of the volume. The fraction of blood volume occupied by cells is termed as the hematocrit, a clinically important parameter. Hematocrit = Cell volume/Totalblood volume One of the reasons that a person’s hematocrit is clinically relevant is that the viscosity of blood increases dramatically with increases in its hematocrit. Recall that fluid viscosity is one physical factor that affects the flow through a tube. Other factors equal, the higher the blood viscosity, the more work the heart has to do to produce any given flow through the vasculature. Blood Cells Blood contains 3 general types of “formed elements”: red cells, white cells, and platelets (see Appendix A). All are formed in bone marrow from a common stem cell. Red cells are by far the most abundant. They are specialized to carry oxygen from the lungs to other tissues by binding oxygen to hemoglobin, an iron-containing heme protein contained within red blood cells. Because of the presence of hemoglobin, blood can transport 40 to 50 times the amount of oxygen that plasma alone could carry. In addition, the hydrogen ion buffering capacity of hemoglobin is vitally important to the blood’s capacity to transport carbon dioxide. A small, but important, fraction of the cells in blood is white cells or leukocytes. Leukocytes are involved in immune processes. Appendix A gives more information on the types and function of leukocytes. Platelets are small cell fragments that are important in the blood-clotting process. Plasma Plasma is the liquid component of blood and, as indicated in Appendix B, is a complex solution of electrolytes and proteins. Serum is the fluid obtained from a blood sample after it has been allowed to clot. For all practical purposes, the composition of serum is identical to that of plasma except that it contains none of the clotting proteins. Inorganic electrolytes (inorganic ions such as sodium, potassium, chloride, and bicarbonate) are the most concentrated solutes in plasma. Of these, sodium and chloride are by far the most abundant and, therefore, are primarily responsible for plasma’s normal osmolarity of approximately 300 mOsm/L. To a first approximation, the “stock” of the plasma soup is a 150-mM solution of sodium chloride. Such a solution is called “isotonic saline” and has many clinical uses as a fluid that is compatible with cells. Plasma normally contains many different proteins. Most plasma proteins can be classified as albumins, globulins, or fibrinogen on the basis of different physical and chemical characteristics used to separate them. More than 100 distinct plasma proteins have been identified and each presumably serves some specific function. Many plasma proteins are involved in blood clotting or immune/defense reactions. Many others are important carrier proteins for a variety of substances including fatty acids, iron, copper, vitamin D, and certain hormones. Proteins do not readily cross capillary walls and, in general, their plasma concentrations are much higher than their concentrations in the interstitial fluid. As will be discussed, plasma proteins play an important osmotic role in transcapillary fluid movement and consequently in the distribution of extracellular volume between the plasma and interstitial compartments. Albumin plays an especially strong role in this regard simply because it is by far the most abundant of the plasma proteins. Plasma also serves as the vehicle for transporting nutrients and waste products. Thus, a plasma sample contains many small organic molecules such as glucose, amino acids, urea, creatinine, and uric acid whose measured values are useful in clinical diagnosis. PERSPECTIVES In this first chapter, we have argued that maintaining bodily homeostasis is the bottom-line task of the cardiovascular system. To maintain homeostasis in any tissue in any given situation, that tissue must receive a blood flow through its capillaries that is matched to support the local current metabolic needs of that tissue. Adequate arterial pressure is necessary to produce tissue blood flow in the first place but arterial pressure is only one factor in achieving adequate tissue blood flow. Constant arterial pressure by itself does not ensure that there will be homeostasis throughout the body. What constant arterial pressure does do is allow an individual organ to control its own blood flow by varying the local resistance to blood flow according to its current metabolic needs. Moreover, this local control allows any organ to regulate its own flow without disturbing the flows through other organs. At this juncture we would also like to draw the reader’s attention to Appendix C, which is a shorthand compilation of many of the key cardiovascular relationships that we have and will encounter in due course. KEY CONCEPTS The primary role of the cardiovascular system is to maintain homeostasis in the interstitial fluid. The physical law that governs cardiovascular operation is that flow through any segment is equal to pressure difference across that segment divided by its resistance to flow, that is,. = ∆P/R. The rate of transport of a substance within the blood (X) is a function of its concentration in the blood [X] and the blood flow rate, that is, =. [X]. The heart pumps blood by rhythmically filling and ejecting blood from the ventricular chambers that are served by passive one-way inlet and outlet valves. Cardiac output (CO) is a function of the heart rate (HR) and stroke volume (SV), that is, CO = HR × SV. Changes in heart rate and stroke volume (and therefore cardiac output) can be accomplished by alterations in ventricular filling and by alterations in autonomic nerve activity to the heart. Blood flow through individual organs is regulated by changes in the diameter of their arterioles. Changes in arteriolar diameter can be accomplished by alterations in sympathetic nerve activity and by variations in local conditions. Blood is a complex suspension of red cells, white cells, and platelets in plasma that is ideally suited to carry gases, salts, nutrients, and waste molecules throughout the system. STUDY QUESTIONS 1–1. Which organ in the body always receives the most blood flow?  1–2. Whenever skeletal muscle blood flow increases, blood flow to other organs must decrease. True or false? 1–3. When a heart valve does not close properly, a sound called a “murmur” can often be detected as the valve leaks. Would you expect a leaky aortic valve to cause a systolic or diastolic murmur? 1–4. Slowing of action potential conduction through the AV node will slow the heart rate. True or false? 1–5. Suppose the diameters of the vessels within an organ increase by 10%. Other factors equal, how would this affect the a. resistance to blood flow through the organ? b. blood flow through the organ? 1–6. The pressure in the aorta is normally about 100 mm Hg, whereas that in the pulmonary artery is normally about 15 mm Hg. A few of your fellow students offer the following alterative hypotheses about why this might be so: a. The right heart pumps less blood than the left heart. b. The right heart rate is slower than the left heart rate. c. The right ventricle is less muscular than the left ventricle. d. The pulmonary vascular bed has less resistance than the systemic bed. e. The stroke volume of the right heart is less than that of the left heart. f. It must be genetics. Which of their suggestions is (are) correct? 1–7. Usually, an individual who has lost a significant amount of blood is weak and does not reason very clearly. Why would blood loss have these effects? 1–8. What direct cardiovascular consequences would you expect from an intravenous injection of norepinephrine? 1–9. What direct cardiovascular effects would you expect from an intravenous injection of a drug that stimulates α -adrenergic receptors but not β -adrenergic receptors? 1–10. Individuals with high arterial blood pressure (hypertension) are often treated with drugs that block β -adrenergic receptors. What is a rationale for such treatment? 1–11. The clinical laboratory reports a serum sodium ion value of 140 mEq/L in a blood sample you have taken from a patient. What does this tell you about the sodium ion concentration in plasma, in interstitial fluid, and in intracellular fluid? 1–12. Explain how it is that the water flow into your kitchen sink changes when you turn the handle on its faucet. 1–13. A common “side effect” of β -blocker therapy is decreased exercise tolerance. Why is this not surprising? 1–14. You need to determine the correct dose of an IV drug that distributes only within the extracellular space. Which of the following values would be the closest estimate of the extracellular fluid volume of a healthy young adult male weighing 100 kg (220 lb)? a. 3 L b. 5 L c. 8 L d. 10 L e. 20 L 1–15. Determine the rate of glucose uptake by an exercising skeletal muscle ( ) from the following data: Arterial blood glucose concentration, [G] a = 50 mg/100 mL Muscle venous blood glucose concentration, [G] v = 30 mg/100 mL Muscle blood flow = 60mL/min 1–16. The Fick principle implies that doubling the flow through an organ will necessarily double the organ’s rate of metabolism (or production) of a substance. True or False? 1–17. Five requirements for normal cardiac pumping action were listed in this chapter. Recall that CO = HR × (EDV − ESV). Use this as a basis for explaining in detail why a lack of each of the requirements would adversely affect CO. 1 Although pressure is most correctly expressed in units of force per unit area, it is customary to express pressures within the cardiovascular system in millimeters of mercury. For example, mean arterial pressure may be said to be 100 mm Hg because it is same as the pressure existing at the bottom of a mercury column 100 mm high. All cardiovascular pressures are expressed relative to atmospheric pressure, which is approximately 760 mm Hg. 2 The basic pumping principle of the heart has a very long evolutionary history. Eons before mammals evolved, bivalve mollusks were using the same principle to pump water through themselves to harvest food energy from microscopic organisms living in that water. Characteristics of Cardiac 2 Muscle Cells OBJECTIVES The student understands the ionic basis of the spontaneous electrical activity of cardiac muscle cells: Describes how membrane potentials are created across semipermeable membranes by transmembrane ion concentration differences. Defines equilibrium potential and knows its normal value for potassium and sodium ions. States how membrane potential reflects a membrane’s relative permeability to various ions. Defines resting potential and action potential. Describes the characteristics of “fast” and “slow” response action potentials. Identifies the refractory periods of the cardiac cell electrical cycle. Defines threshold potential and describes the interaction between ion channel conditions and membrane potential during the depolarization phase of the action potential. Defines pacemaker potential and describes the basis for rhythmic electrical activity of cardiac cells. Names the important ion channels involved in the permeability alterations during the various phases of the cardiac cycle. The student knows the normal process of cardiac electrical excitation: Describes gap junctions and their role in cardiac excitation. Describes the normal pathway of action potential conduction through the heart.  Indicates the timing at which various areas of the heart are electrically excited and identifies the characteristic action potential shapes and conduction velocities in each major part of the conduction system. States the relationship between electrical events of cardiac excitation and the P, QRS, and T waves, the PR and QT intervals, and the ST segment of the electrocardiogram. The student understands the factors that control the heart rate and action potential conduction in the heart: States how diastolic potentials of pacemaker cells can be altered to produce changes in the heart rate. Describes how cardiac sympathetic and parasympathetic nerves alter the heart rate and conduction of cardiac action potentials. Defines the terms chronotropic and dromotropic. The student understands the contractile processes of cardiac muscle cells: Lists the subcellular structures responsible for cardiac muscle cell contraction. Defines and describes the excitation–contraction process. Defines isometric, isotonic, and afterloaded contractions of the cardiac muscle. Identifies the influence of altered preload on the tension- producing and shortening capabilities of the cardiac muscle. Describes the influence of altered afterload on the shortening capabilities of the cardiac muscle. Defines the terms contractility and inotropic state and describes the influence of altered contractility on the tension-producing and shortening capabilities of the cardiac muscle. Describes the effect of altered sympathetic neural activity on the cardiac inotropic state. States the relationships between ventricular volume and muscle length, between intraventricular pressure and muscle tension and the law of Laplace. Cardiac muscle cells are responsible for providing the power to drive blood through the circulatory system. Coordination of their activity depends on an electrical stimulus that is regularly initiated at an appropriate rate and reliably conducted through the entire heart. Mechanical pumping action depends on a robust contraction of the muscle cells that results in repeating cycles of tension development, shortening, and relaxation. In addition, mechanisms to adjust the excitation and contraction characteristics must be available to meet the changing demands of the circulatory system. This chapter focuses on these electrical and mechanical properties of cardiac muscle cells that underlie normal heart function. ELECTRICAL ACTIVITY OF CARDIAC MUSCLE CELLS In all striated muscle cells, contraction is triggered by a rapid voltage change called an action potential that occurs on the cell membrane. Cardiac muscle cell action potentials differ sharply from those of skeletal muscle cells in 3 important ways that promote synchronous rhythmic excitation of the heart: (1) they can be self-generating; (2) they are conducted directly from cell to cell; and (3) they have long duration, which precludes fusion of individual twitch contractions. To understand these special electrical properties of the cardiac muscle and how cardiac function depends on them, the basic electrical properties of excitable cell membranes must first be examined. Membrane Potentials All cells have an electrical potential (voltage) across their membranes. Such transmembrane potentials are caused by a separation of electrical charges across the membrane itself. The only way that the transmembrane potential can change is for electrical charges to move across (i.e., current to flow through) the cell membrane. There are 2 important corollaries to this statement: (1) the rate of change of transmembrane voltage is directly proportional to the net current across the membrane; and (2) transmembrane voltage is stable (i.e., unchanging) only when there is no net current across the membrane. Unlike a wire, current across cell membranes is not carried by electrons but by the movement of ions through the cell membrane. The 3 ions that are the most important determinants of cardiac transmembrane potentials are sodium (Na +) and calcium (Ca 2 +), which are more concentrated in the extracellular fluid than they are inside cells, and potassium (K +), which is more concentrated in intracellular than extracellular fluid. (See Appendix B for normal values of many constituents of adult human plasma.) In general, such ions are very insoluble in lipids. Consequently, they cannot pass into or out of a cell through the lipid bilayer of the membrane itself. Instead, these ions cross the membrane only via various protein structures that are embedded in and span across the lipid cell wall. There are 3 general types of such transmembrane protein structures that are involved in ion movement across the cell membrane: (1) ion channels; (2) ion exchangers; and (3) ion pumps. 1 All are very specific for particular ions. For example, a “sodium channel” is a transmembrane protein structure that allows only Na + ions to pass into or out of a cell according to the net electrochemical forces acting on Na + ions. The subsequent discussion concentrates on ion channel operation because ion channels (as opposed to exchangers and pumps) are responsible for the resting membrane potential and for the rapid changes in membrane potential that constitute the cardiac cell action potential. Ion channels are under complex control and can be “opened,” “closed,” or “inactivated.” The net result of the status of membrane channels to a particular ion is commonly referred to as the membrane’s permeability to that ion. For example, “high permeability to sodium” implies that many of the Na + ion channels are in their open state at that instant. Precise timing of the status of ion channels accounts for the characteristic membrane potential changes that occur when cardiac cells are activated. Figure 2–1 shows how ion concentration differences can generate an electrical potential across the cell membrane. Consider first, as shown at the top of this figure, a cell that (1) has K + more concentrated inside the cell than outside, (2) is permeable only to K + (i.e., only K + channels are open), and (3) has no initial transmembrane potential. Because of the concentration difference, K + ions (positive charges) will diffuse out of the cell. Meanwhile, negative charges, such as protein anions, cannot leave the cell because the membrane is impermeable to them. Thus, the K + efflux will make the cytoplasm at the inside surface of the cell membrane more electrically negative (deficient in positively charged ions) and at the same time make the interstitial fluid just outside the cell membrane more electrically positive (rich in positively charged ions). K + ion, being positively charged, is attracted to regions of electrical negativity. Therefore, when K + diffuses out of a cell, it creates an electrical potential across the membrane that tends to attract it back into the cell. There exists one membrane potential called the potassium equilibrium potential at which the electrical forces tending to pull K + into the cell exactly balance the concentration forces tending to drive K + out. When the membrane potential has this value, there is no net movement of K + across the membrane. With the normal concentrations of approximately 145 mM K + inside cells and 4 mM K + in the extracellular fluid, the K + equilibrium potential is roughly −90 mV (more negative inside than outside by nine- hundredths of a volt). 2 A membrane that is permeable only to K + will inherently and rapidly (essentially instantaneously) develop the potassium equilibrium potential. In addition, membrane potential changes require the movement of so few ions that concentration differences between the intra- and extracellular fluid compartments are not significantly affected by the process. Figure 2–1. Electrochemical basis of membrane potentials. As depicted in the bottom half of Figure 2–1, similar reasoning shows how a membrane permeable only to Na + would have the sodium equilibrium potential across it. The sodium equilibrium potential is approximately +70 mV, with the normal extracellular Na + concentration of 140 mM and intracellular Na + concentration of 10 mM. Real cell membranes, however, are never permeable to just Na + or just K +. When a membrane is permeable to both of these ions, the membrane potential will lie somewhere between the Na + equilibrium potential and the K + equilibrium potential. Just what membrane potential will exist at any instant depends on the relative permeability of the membrane to Na + and K +. The more permeable the membrane is to K + than to Na +, the closer the membrane potential will be to −90 mV. Conversely, when the permeability to Na + is high relative to the permeability to K +, the membrane potential will be closer to +70 mV. 3 A stable membrane potential that lies between the sodium and potassium equilibrium potentials implies that there is no net current across the membrane. This situation may well be the result of opposite but balanced sodium and potassium currents across the membrane. Because of low or unchanging permeability or low concentration, roles played by ions other than Na + and K + in determining membrane potential are usually minor and often ignored. However, as discussed later, calcium ions (Ca 2 +) do participate in the cardiac muscle action potential. Like Na +, Ca 2 + is more concentrated outside cells than inside. The equilibrium potential for Ca 2 + is approximately +100 mV, and the cell membrane tends to become more positive on the inside when the membrane’s permeability to Ca 2 + rises. Under resting conditions, most heart muscle cells have membrane potentials that are quite close to the potassium equilibrium potential. Thus, both electrical and concentration gradients favor the entry of Na + and Ca 2 + into the resting cell. Left unchecked, this slow leak of Na + and Ca 2 + into the cell and K + out of the cell would ultimately destroy the transmembrane potential. However, the very low permeability of the resting membrane to Na + and Ca 2 + (in combination with a Na +–Ca 2 + exchanger and an energy-requiring sodium–potassium pump) prevents Na + and Ca 2 + from gradually accumulating inside the resting cell. 4 , 5 Cardiac Muscle Cell Action Potentials Action potentials of cells from different regions of the heart are not identical but have varying characteristics that are important to the overall process of cardiac excitation. Some cells within a specialized conduction system have the ability to act as pacemakers and to spontaneously initiate action potentials, whereas ordinary cardiac muscle cells do not (except under unusual conditions). Basic membrane electrical features of an ordinary cardiac muscle cell and a cardiac pacemaker-type cell are shown in Figure 2–2. Action potentials from these cell types are referred to as “fast-response” and “slow- response” action potentials, respectively. Figure 2–2. Time course of membrane potential ( A and B) and ion permeability changes ( C and D) that occur during “fast-response” ( left) and “slow-response” ( right) action potentials. As shown in Figure 2–2A, fast-response action potentials are characterized by a rapid depolarization (phase 0) with a substantial overshoot (positive inside voltage), a rapid reversal of the overshoot potential (phase 1), a long plateau (phase 2), and a repolarization (phase 3) to a stable, high (i.e., large negative) resting membrane potential (phase 4). In comparison, the slow-response action potentials are characterized by a slower initial depolarization phase, a lower amplitude overshoot, a shorter and less stable plateau phase, and a repolarization to an unstable, slowly depolarizing “resting” potential ( Figure 2–2B). The unstable resting potential seen in pacemaker cells with slow-response action potentials is variously referred to as phase 4 depolarization, diastolic depolarization, or pacemaker potential. Such cells are usually found in the sinoatrial (SA) and atrioventricular (AV) nodes. As indicated at the bottom of Figure 2–2A, cells are in an absolute refractory state during most of the action potential (i.e., they cannot be stimulated to fire another action potential). Near the end of the action potential, the membrane is relatively refractory and can be reexcited only by a larger-than-normal stimulus. This long refractory state precludes summated or tetanic contractions from occurring in normal cardiac muscle. Immediately after the action potential, the membrane is transiently hyperexcitable and is said to be in a “vulnerable” or “supranormal” period. Similar alterations in membrane excitability occur during slow action potentials but are not well characterized at present. Recall that the membrane potential of any cell at any given instant depends on the relative permeability of the cell membrane to specific ions. As in all excitable cells, cardiac cell action potentials are the result of large, rapid and transient changes in the ionic permeability of the cell membrane that are triggered by an initial small, localized depolarization and then propagated over the entire cell membrane. Figure 2–2C and 2–2D indicates the changes in the membrane’s permeabilities to K+, Na+, and Ca2+ that produce the various phases of the fast- and slow-response action potentials.6 Note that during the resting phase, the membranes of both types of cells are more permeable to K+ than to Na+ or Ca2+. Therefore, the membrane potentials are close to the potassium equilibrium potential (of −90 mV) during this period. In pacemaker-type cells, at least 3 mechanisms are thought to contribute to the slow depolarization of the membrane observed during the diastolic interval. First, there is a progressive decrease in the membrane’s permeability to K + during the resting phase. Second, the permeability to Na + increases slowly. (This gradual increase in the Na +/K + permeability ratio will cause the membrane potential to move slowly away from the K + equilibrium potential (−90 mV) in the direction of the Na + equilibrium potential.) Third, there is a slight increase in the permeability of the membrane to calcium ions late in diastole, which results in an inward movement of these positively charged ions and also contributes to the diastolic depolarization. These permeability changes result in a specific current that occurs during diastole called the i-funny ( i f) current. When the membrane potential depolarizes to a certain threshold potential in either type of cell, major rapid alterations in the permeability of the membrane to specific ions are triggered. Once initiated, these permeability changes cannot be stopped and they proceed to completion. The characteristic rapid rising phase of the fast-response action potential is a result of a sudden increase in Na + permeability. This produces what is referred to as the fast inward current of Na + and causes the membrane potential to move rapidly toward the sodium equilibrium potential. As indicated in Figure 2–2C, this period of very high sodium permeability (phase 0) is short-lived. A very brief increase in potassium permeability then occurs (not shown in Figure 2–2C) that allows a brief outward-going potassium current ( iTo) and results in a small non- sustained repolarization after the peak of the action potential (phase 1). Development and maintenance of a prolonged depolarized plateau state (phase 2) is accomplished by the interactions of at least 2 separate processes: (1) a sustained reduction in K + permeability and (2) a slowly developed and sustained increase in the membrane’s permeability to Ca 2 +. In addition, under certain conditions, the electrogenic action of a Na +– Ca 2 + exchanger (in which 3 Na + ions move into the cell in exchange for a single Ca 2 + ion moving out of the cell) may contribute to the maintenance of the plateau phase of the cardiac action potential. The initial fast inward current is small (or even absent) in cells that have slow-response action potentials ( Figure 2–2D). Therefore, the initial depolarization phase of these action potentials is somewhat slower than that of the fast-response action potentials and is primarily a result of an inward movement of Ca 2 + ions. In both types of cells, the membrane is repolarized (during phase 3) to its original resting potential as the K + permeability increases to its high resting value and the Ca 2 + and Na + permeabilities return to their low resting values. These late permeability changes produce what is referred to as the delayed outward current. The overall smoothly graded permeability changes that produce action potentials are the net result of alterations in each of the many individual ion channels within the plasma membrane of a single cell. 7 These ion channels are generally made up of very long polypeptide chains that loop repeatedly across the cell membrane. These loops form a hollow conduction channel between the intracellular and extracellular fluids that are structurally quite specific for a particular ion. These channels can exist in 1 of 3 conformational states: open, closed, or inactivated. The status of the channels can be altered by configurational changes in certain subunits of the molecules within the channel (referred to as “gates” or plugs) so that when open, ions move down their electrochemical gradient either into or out of the cell (high permeability) and when closed or inactivated, no ions can move (low permeability). The specific mechanisms that control the operation of these channels during the action potential are not fully understood. Certain types of channels are called voltage-gated channels (or voltage-operated channels) because their probability of being open varies with membrane potential. Another type of channels, called ligand-gated channels (or receptor- operated channels), are activated by certain neurotransmitters or other specific signal molecules. Table 2–1 lists a few of the major important currents and channel types involved in cardiac cell electrical activity. The number of well-described ion channels in cardiac muscle is rapidly increasing and abnormalities in these channels (channelopathies) are now known to be responsible for a variety of excitation abnormalities. Our oversimplified description of channel function below is an effort to provide some basic understanding without the many complicating features of the electrical excitation process. Table 2–1. Characteristics of Important Cardiac Ion Channels in Order of Their Participation in an Action Potential  Some of the voltage-gated channels respond to a sudden-onset, sustained change in membrane potential by only a brief period of activation. However, changes in membrane potential of slower onset, but the same magnitude, may fail to activate these channels at all. To explain such behavior, it is postulated that a given channel has 2 independently operating “gates”—an activation gate and an inactivation gate—both of which must be open for the channel as a whole to be open. Both these gates respond to changes in membrane potential but do so with different voltage sensitivities and time courses. These concepts are illustrated in Figure 2–3. (For simplicity, a single Na + channel and Ca 2 + channel are shown and K + channels are ignored). In the resting state, with the membrane polarized to approximately −80 mV, the activation gate of the fast Na + channel is closed, but its inactivation gate is open ( Figure 2–3A). With a rapid depolarization of the membrane to threshold, the Na + channels will be activated strongly to allow an inrush of positive sodium ions that further depolarizes the membrane and thus accounts for the rising phase of a “fast” response action potential, as illustrated in Figure 2–3B. This occurs because the activation gate responds to membrane depolarization by opening more quickly than the inactivation gate responds by closing. Thus, a small initial rapid depolarization to threshold is followed by a brief, but strong, period of Na + channel activation wherein the activation gate is open but the inactivation gate is yet to close. Within a few milliseconds, however, the inactivation gates of the fast sodium channels close and shut off the inward movement of Na +. After a brief delay, the large membrane depolarization of the rising phase of the fast action potential causes the activation gate of the L-type Ca 2 + channel to open. This permits the slow inward movement of Ca 2 + ions, which helps maintain the depolarization through the plateau phase of the action potential ( Figure 2–3C). Ultimately, repolarization occurs because of both a delayed inactivation of the Ca 2 + channel (by closure of the inactivation gates) and a delayed opening of K + channels (which are not shown in Figure 2–3). The inactivation gates of sodium channels remain closed during the plateau phase and the remainder of the action potential, effectively inactivating the Na + channel. This sustained sodium channel inactivation, combined with activation of calcium channels and the delay in opening of potassium channels, accounts for the long plateau phase and the long cardiac refractory period, which lasts until the end of phase 3. With repolarization, both gates of the sodium channel return to their original position and the channel is now ready to be reactivated by a subsequent depolarization. Multiple factors in addition to membrane voltage can influence the membrane ionic permeability and normal operation of ion channels. For example, high intracellular Ca 2 + concentration during systole contributes to activation of certain K + channels and increases the rate of repolarization. Sympathetic and parasympathetic neural input can influence the status of some voltage-gated channels and cause activation or suppression of other ligand-gated channels. In addition, mechano-gated and mechano-modultated channels may be activated by myocyte stretch or myocyte volume changes and can influence membrane permeability to K +, Na +, and Ca 2 +. Figure 2–3. A conceptual model of cardiac membrane fast sodium and slow calcium ion channels: at rest ( A), during the initial phases of the fast-response ( B and C), and the slow-response action potentials ( D and E). “Activation” gates (m and d) are hatched and “inactivation” gates (h and f) are stippled. The slow-response action potential shown in the right half of Figure 2– 3 differs from the fast-response action potential primarily because of the lack of a strong activation of the fast Na + channel at its onset. This accounts for the slow rate of rise of the action potential in these cells. The slow diastolic depolarization that occurs in these pacemaker-type cells is primarily a result of an inward current ( I funny) flowing through a channel that is an isoform of the family of nonselective cation hyperpolarization- activated, cyclic nucleotide-gated (HCN) channels. This channel is activated at the end of the repolarization phase and promotes a slow sodium, potassium, and calcium influx that gradually depolarizes the cells during diastole. This slow diastolic depolarization gives the inactivating h gates of many of the fast sodium channels time to close before threshold is even reached ( Figure 2–3D). Thus, in a slow-response action potential, there is no initial period where all the fast sodium channels of a cell are essentially open at once. The depolarization beyond threshold during the rising phase of the action potential in these “pacemaker” cells is slow and caused primarily by the influx of Ca 2 + through slow L-type channels ( Figure 2–3E). Although cells in certain areas of the heart typically have fast-type action potentials and cells in other areas normally have slow-type action potentials, it is important to recognize that all cardiac cells are potentially capable of having either type of action potential, depending on their maximum resting membrane potential and how fast they depolarize to the threshold potential. As we shall see, rapid depolarization to the threshold potential is usually an event forced on a cell by the occurrence of an action potential in an adjacent cell. Slow depolarization to threshold occurs when a cell itself spontaneously and gradually loses its resting polarization, which normally happens only in the SA or AV node. A chronic moderate depolarization of the resting membrane (caused, e.g., by moderately high extracellular K + concentrations of 5–7 mM) can inactivate the fast channels (by closing the h gates) without inactivating the slow L-type Ca 2 + channels. Under these conditions, all cardiac cell action potentials will be of the slow type. Large, sustained depolarizations (as might be caused by very high extracellular K + concentration such as more than 8 mM), however, can inactivate both the fast and slow channels and thus make the cardiac muscle cells completely inexcitable. Conduction of Cardiac Action Potentials Action potentials are initiated at a local site on a cardiac myocyte and then conducted over the surface of individual cells. This occurs because active depolarization in any one area of the membrane produces local currents that pass through the intracellular and extracellular fluids. These currents passively depolarize immediately adjacent areas of the membrane to their voltage thresholds to initiate an action potential at this new site. In the heart, cardiac muscle cells are branching and connected end-to- end with neighboring cells at structures called intercalated disks. These disks contain the following: (1) firm mechanical attachments between adjacent cell membranes by proteins called adherins in structures called desmosomes and (2) low-resistance electrical connections between adjacent cells through channels formed by proteins called connexin in structures called gap junctions. Figure 2–4 shows schematically how these gap junctions allow action potential propagation from cell to cell. Cells B, C, and D are shown in the resting phase with more negative charges inside than outside. Cell A is shown in the plateau phase of an action potential and has more positive charges inside than outside. Because of the gap junctions, electrostatic attraction can cause a local current flow (ion movement) between the depolarized membrane of active cell A and the polarized membrane of resting cell B, as indicated by the arrows in the figure. This ion movement depolarizes the membrane of cell B. Once the local currents from active cell A depolarize the membrane of cell B near the gap junction to the threshold level, an action potential will be triggered at that site and will be conducted over cell B. Because cell B branches (a common morphological characteristic of cardiac muscle fibers), its action potential will evoke action potentials on cells C and D. This process is continued through the entire myocardium. Thus, an action potential initiated at any site in the myocardium will be conducted from cell to cell throughout the entire heart. The speed at which an action potential propagates through a region of cardiac tissue is called the conduction velocity. The conduction velocity varies considerably in different areas in the heart and is determined by 3 variables. (1) The diameter of the muscle fiber involved. Thus, conduction over small-diameter cells in the AV node is significantly slower than conduction over large-diameter cells in the ventricular Purkinje system. (2) The intensity of the local depolarizing currents, which are in turn directly determined by the rate of rise of the action potential. Rapid action potential depolarization favors rapid conduction to the neighboring segment or cell. (3) The capacitive and/or resistive properties of the cell membranes, gap junctions, and cytoplasm. Electrical characteristics of gap junctions can be influenced by external conditions that promote phosphorylation or dephosphorylation of the connexin proteins. Details of the overall consequences of the variable cardiac conduction rates are shown in Figure 2–5. As noted earlier, specific electrical adaptations of various cells in the heart are reflected in the characteristic shape of their action potentials that are shown in the right half of Figure 2– 5. Note that the action potentials shown in Figure 2–5 have been positioned to indicate the time when the electrical impulse that originates in the SA node reaches other areas of the heart. Cells of the SA node act as the heart’s normal pacemaker and determine the heart rate. This is because the slow spontaneous diastolic depolarization of the membrane is normally most rapid in SA nodal cells, and therefore, the cells in this region reach their threshold potential and fire before cells elsewhere. Figure 2–4. Local currents and cell-to-cell conduction of cardiac muscle cell action potentials. Figure 2–5. Time records of electrical activity at different sites in the heart wall: single-cell voltage recordings (traces A to G) and lead II electrocardiogram. The action potential initiated by an SA nodal cell first spreads progressively throughout the branching and interconnected cardiac muscle cells of the atrial wall. Action potentials from cells in 2 different regions of the atria are shown in Figure 2–5: one close to the SA node and one more distant from the SA node. Both cells have similarly shaped fast response- type action potentials, but their temporal displacement reflects the fact that it takes some time for the impulse to spread over the atria. As shown in Figure 2–5, action potential conduction is greatly slowed as it passes through the AV node. This is because of the small size of the AV nodal cells and the slow rate of rise of their action potentials. Since the AV node delays the transfer of the cardiac excitation from the atria to the ventricles, atrial contraction can contribute to ventricular filling before the ventricles begin to contract. Note also that AV nodal cells have a faster spontaneous depolarization during the diastolic period than other cells of the heart except those of the SA node. For this reason, the AV node is sometimes referred to as a latent pacemaker, and in many pathological situations, it (rather than the SA node) controls the heart rhythm. This situation is referred to as a “nodal” rhythm as distinguished from the normal “sinus” rhythm. Because of sharply rising action potentials and other factors, such as large cell diameters, electrical conduction is extremely rapid in Purkinje fibers. This allows the Purkinje system to transfer the cardiac impulse to cells in many areas of the ventricle nearly in unison. Action potentials from muscle cells in 2 areas of the ventricle are shown in Figure 2–5. Because of the high conduction velocity in ventricular tissue, there is only a small discrepancy in their time of onset. Note in Figure 2–5 the ventricular cells that are the last to depolarize have shorter-duration action potentials and thus are the first to repolarize. The physiological importance of this behavior is not clear, but it does have an influence on the electrocardiograms discussed in Chapter 4. Electrocardiogram (ECG aka EKG) Fields of electrical potential caused by the electrical activity of the heart extend through the extracellular fluid of the body and can be measured with electrodes placed on the body surface. Electrocardiography provides a record of how the voltage between 2 points on the body surface changes with time as a result of the electrical events of the cardiac cycle. At any instant of the cardiac cycle, the electrocardiogram indicates the net electrical field that is the summation of many weak electrical fields being produced by voltage changes occurring on individual cardiac cells at that instant. When a large number of cells are simultaneously depolarizing or repolarizing, large voltages are observed on the electrocardiogram. Because the electrical impulse spreads through the heart tissue in a consistent pathway, the temporal pattern of voltage change recorded between 2 points on the body surface is also consistent and repeats itself with each heart cycle. The lower trace of Figure 2–5 represents a typical recording of the voltage changes normally measured between the right arm and the left leg as the heart goes through 2 cycles of electrical excitation; this record is called a lead II electrocardiogram and is discussed in detail in Chapter 4. The major features of an electrocardiogram are indicated on this record and include the P wave, the PR interval, the QRS complex, the QT interval, the ST segment, and the T wave. The P wave corresponds to atrial depolarization; the PR interval to the conduction time through the atria and AV node; the QRS complex to ventricular depolarization; the ST segment to the plateau phase of ventricular action potentials; the QT interval to the total duration of ventricular systole; and the T wave to ventricular repolarization. (See Chapters 4 and 5 for further information about electrocardiograms.) Control of Heart Beating Rate Normal rhythmic contractions of the heart occur because of spontaneous electrical pacemaker activity (automaticity) of cells in the SA node. The interval between heartbeats (and thus the heart rate) is determined by how long it takes the membranes of these pacemaker cells to spontaneously depolarize during the diastolic interval to the threshold level. The SA nodal cells fire at a spontaneous or intrinsic rate (≈100 beats/min) in the absence of any outside influences. Outside influences are required, however, to increase or decrease automaticity from its intrinsic level. Figure 2–6. The effect of sympathetic and parasympathetic activity on cardiac pacemaker potentials. The 2 most important outside influences on automaticity of SA nodal cells come from the autonomic nervous system. Fibers from both the sympathetic and parasympathetic divisions of the autonomic system terminate on cells in the SA node, and these fibers can modify the intrinsic heart rate. Activating the cardiac sympathetic nerves (increasing cardiac sympathetic tone) increases the heart rate. Increasing the cardiac parasympathetic tone slows the heart rate. As shown in Figure 2–6, both the parasympathetic and sympathetic nerves influence the heart rate by altering the course of spontaneous diastolic depolarization of the resting potential in SA pacemaker cells. Cardiac parasympathetic fibers, which travel to the heart through the vagus nerves, release the transmitter substance acetylcholine on SA nodal cells. Acetylcholine increases the permeability of the resting membrane to K + and decreases the diastolic i f current flowing through the HCN channels. 8 As indicated in Figure 2–6, these changes have 2 effects on the resting potential of cardiac pacemaker cells: (1) they cause an initial hyperpolarization of the resting membrane potential by bringing it closer to the K + equilibrium potential and (2) they slow the rate of spontaneous depolarization of the resting membrane. Both of these effects increase the time between beats by prolonging the time required for the resting membrane to depolarize to the threshold level. Because there is normally some continuous tonic activity of cardiac parasympathetic nerves, the normal resting heart rate is approximately 70 beats/min which is significantly slower than the intrinsic rate of ~100 beats/min. Sympathetic nerves release the transmitter substance norepinephrine on cardiac cells. In addition to other effects discussed later, norepinephrine acts on SA nodal cells to increase the inward currents ( i f) carried by Na + and by Ca 2 + through the HCN channels during the diastolic interval. 9 These changes will increase the heart rate by increasing the rate of diastolic depolarization as shown in Figure 2–6. In addition to sympathetic and parasympathetic nerves, there are many (albeit usually less important) factors that can alter the heart rate. These include a number of ions, circulating hormones, and various drugs as well as physical influences such as body temperature and atrial wall stretch. All act by altering the time required for the resting membrane to depolarize to the threshold potential. An abnormally high concentration of Ca 2 + in the extracellular fluid, for example, tends to decrease the heart rate by shifting the threshold potential. Factors that increase the heart rate are said to have a positive chronotropic effect. Those that decrease the heart rate have a negative chronotropic effect. Besides their effect on the heart rate, autonomic fibers also influence the conduction velocity of action potentials through the heart. Increases in sympathetic activity increase conduction velocity (have a positive dromotropic effect), whereas increases in parasympathetic activity decrease conduction velocity (have a negative dromotropic effect). These dromotropic effects are primarily a result of autonomic influences on the initial rate of depolarization of the action potential and/or influences on conduction characteristics of gap junctions between cardiac cells. These effects are most notable at the AV node and influence the duration of the PR interval of the ECG. MECHANICAL ACTIVITY OF THE HEART Contraction of the cardiac muscle cell is initiated by a membrane action potential acting on intracellular organelles to evoke tension generation and/or shortening of the cell. In this section, we describe (1) the subcellular processes involved in coupling the excitation to the contraction of the cell (EC coupling) and (2) the mechanical properties of cardiac cells. Cardiac Muscle Cell Contractile Apparatus Basic histological features of cardiac muscle cells are quite similar to those of skeletal muscle cells. These shared features include: (1) An extensive myofibrillar structure made up of parallel interdigitating thick and thin filaments arranged in serial units called sarcomeres, which are responsible for the mechanical processes of shortening and tension development. Proteins making up the thick and thin filaments are collectively referred to as “contractile proteins.” The thick filament consists of a protein called myosin, which has a long straight tail with 2 globular heads each of which contains an ATP-binding site and an actin-binding site; light chains are loosely associated with the myosin heads and their phosphorylation may regulate (or modulate) actin binding. The thin filament consists of several proteins including actin—2 α- helical strands of polymerized subunits (g-actin) extending from the Z lines. Sites along the actin filament interact with the heads of myosin molecules to make deformable cross-bridges with the thick filaments. Thin filaments also contain tropomyosin—a regulatory fibrous-type protein lying in the groove of the actin α-helix, which prevents actin from interacting with myosin when the muscle is at rest; and troponin —a regulatory protein consisting of 3 subunits ( troponin C, which binds calcium ions during activation and initiates the configurational changes in the regulatory proteins that expose the actin site for cross- bridge formation; troponin T, which anchors the troponin complex to tropomyosin; and troponin I, which participates in the inhibition of actin–myosin interaction at rest). The giant macromolecule, titin, extends from the Z disk to the M line in the middle of each sarcomere and provides a continuous filament network in the sarcomeres extending the length of the cell. It contributes significantly to the passive stiffness of cardiac muscle over its normal working range. Phosphorylation of titin can alter the passive elastic properties of cardiac muscle. (2) A complex internal compartmentation of the myocyte cytoplasm by an intracellular membrane system called the sarcoplasmic reticulum (SR). This compartment actively sequesters calcium during the resting phase with the help of the sarco/endoplasmic reticulum Ca 2 +- ATPase (SERCA) and calcium-binding storage proteins within the SR, the most abundant of which is calsequestrin. (3) Regularly spaced, extensive invaginations of the cell membrane (sarcolemma), called T tubules. These structures carry the action potential signal to the inner parts of the cell and appear to be connected to part